This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Alpha-synuclein (aS) is a highly conserved presynaptic protein that participates in synaptic strength maintenance and dopamine homeostasis. It is also involved in regulation of intracellular dopamine levels at several points of control. However, accumulation of aS amyloid fibrils was implicated as the major reason in the development of Parkinson's disease. The three single-point mutations in a-synuclein, namely, A30P, A53T, and E46K, (as well as a triplication of the aS gene) have been linked to a rare familial form of Parkinson's disease (PD). On the other hand the vast majority of Lewy body-related disease cases is sporadic and involves the wild type of aS. Normal functions of [unreadable]S involve protein-membrane interactions upon which the protein undergoes transformations from disordered structure in cytosol to highly helical one in membrane-bound state. Pulsed dipolar ESR was already successfully applied to characterize the structure of wild type aS bound to SDS micelles and phispholipid membranes [1, 2]. We have undertaken a detailed study on the structural properties of PD-linked mutants A30P, E46K and A53T in membrane-bound state, aiming to elucidate eventual differences among wild type aS and its PD-linked derivates. The later might be important to understand the mechanism of PD. We also studied the structure of all aSs in free state in solution.